Heat shock protein 110 improves the anti-tumor effects of the cytotoxic T lymphocyte epitope E7 in mice

Ren, Faliang; Xu, Yunsheng; Mao, Liwei; Ou, Rongying; Ding, Zhenzhen; Zhang, Xueqi; Tang, Jun; Li, Bingxu; Jia, Zhengcai; Tian, Zhiqiang; Ni, Bing; Wu, Yuzhang

doi:10.4161/cbt.9.2.10391

Cited by 21 publications

(21 citation statements)

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“…Specific cellular immunity mediated by CTL plays a key role in cancer immunity. Effector T cells mainly recognize CTL epitopes that are bound to MHC-I molecules to induce cytotoxic cytotoxicity (16). HLA-I molecules are key to antigen presentation and activation of T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it is important to study the HPV58 E6 and E7 HLA-A2-restricted CTL epitope peptide in Chinese population. At present, some HLA-A2 (+) CTL epitopes in HPV16 E7 protein, such as E7 [11][12][13][14][15][16][17][18][19] and E7 49-57, have been identified and accepted (18)(19)(20). At present, many studies have confirmed the effectiveness of these epitopes as antigen targets (21)(22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

“…gov/molbio/hla_bind/; SYFPEITH, http://www.syfpeithi.de/; and epitope prediction and analysis tools, http://tools.immune epitope.org/main/ (27). After a comprehensive analysis, we preliminarily identified 6 CTL antigen peptides in HPV58 E7 that were subsequently named P1 (E7 7-15 : TLREYILDL), P2 (E7 [14][15][16][17][18][19][20][21][22] : DLHPEPTDL), P3 (E7 69-77 : CINSTTTDV), and P4 (E7 72-80 : STTTDVRTL), P5 (E7 79-87 : TLQQLLMGT), P6 (E7 83-91 : LLMGTCTIV).…”

Section: Discussionmentioning

confidence: 99%

“…High risk human papilloma virus (HPV) has been confirmed as a dominant factor responsible for several anogenital diseases, particularly cervical intraepithelial neoplasia (CIN) and cervical carcinoma (1). Of the more than two hundred HPV genotypes, 16,18,31,45,52 and 58 are six particularly important, as they are highly correlated with more than 90% of cervical carcinoma cases (2)(3)(4). Persistent infection with high risk HPV is the primary factor responsible for cervical cancer (3,4).…”

Section: Introductionmentioning

confidence: 99%

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Prediction and identification of human leukocyte antigen‑A2‑restricted cytotoxic T lymphocyte epitope peptides from the human papillomavirus 58 E7 protein

Wang

Chen

et al. 2018

Oncol Lett

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Persistent infection with high-risk human papilloma virus (HPV) is the primary cause of cervical intraepithelial neoplasia (CIN) and cervical carcinoma. HPV58 is the third most common HPV genotype in China after HPV16 and HPV18. HPV E6 and E7 are oncoproteins and are constitutively expressed in HPV-associated cancer cells, therefore they are considered to be ideal target antigens for immunotherapy, including HPV therapeutic vaccine. In the present study, human leukocyte antigen (HLA)-A2-restricted cytotoxic T lymphocyte (CTL) epitope peptides were predicted and screened from HPV58 E7 antigen and their immunogenicity was subsequently determined. A total of 6 HLA-A2-binding peptides derived from HPV58 E7 were predicted and selected using 3 different prediction programs. A negative control peptide and PBS were used as two negative controls. Peripheral blood mononuclear cells (PBMCs) with HLA-A2(+) allele were used to detect the specific cellular immune response among the 6 predicted peptides by enzyme-linked immunospot assay (ELISOPT). Following preliminary screening for the predicted peptides, the antigenicity of the peptide HPV58 E7 was further assessed by an immunoassay to a vaccine contained HPV58 E7 antigen. Specific humoral and cellular immunity were detected using the peptide HPV58 E7 as the specific antigen. A total of 6 peptides from HPV58 E7 protein were predicted and subsequently named P1 (E7: TLREYILDL), P2 (E7: DLHPEPTDL), P3 (E7: CINSTTTDV), and P4 (E7: STTTDVRTL), P5 (E7: TLQQLLMGT) and P6 (E7: LLMGTCTIV). In the ELISPOT assay on HLA-A2 (+) human PBMCs, interferon (IFN)-γ-production was evident in the P2 and P4 groups. The average numbers of IFN-γ associated spots in the P2 and P4 groups was 50.61±5.37 spot-forming cells (SFC)/1×10 and 266±34.42 SFC/1×10, respectively. The numbers of spots in the two peptides were significantly increased compared with the other 4 peptides and the control groups (P<0.05). In the further antigenicity verification of P4 (HPV58 E7), the peptide only stimulated the humoral immune response of the AD-HPV16/18/58 mE6E7 vaccine containing HPV58 E7 antigen. Compared with the 2 negative control groups (1:400), the antibody titers of the vaccine group (1:25,600) were significantly increased (P<0.05). In cellular immunoassays the average number of IFN-γ associated spots was 143.3±32.13 SFC/1×10 in the vaccine group, which was significantly enhanced compared with the PBS group (8±5.29 SFC/1×10; P<0.01) and the AD-NC group (28±5.13 SFC/1×10; P<0.01). The peptide HPV58 E7 (STTTDVRTL) displayed sufficient antigenicity to a vaccine contained HPV58 E7 antigen. Therefore, HPV58 E7 peptide may be considered as a candidate epitope peptide for the construction of HPV58 peptide vaccines.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prediction and identification of human leukocyte antigen‑A2‑restricted cytotoxic T lymphocyte epitope peptides from the human papillomavirus 58 E7 protein

Wang

Chen

et al. 2018

Oncol Lett

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“…The mouse H2-D b -restricted CTL epitope, E7 49-57 (short peptide spanning the 49th to 57th amino acid residues in the E7 protein; RAHYNIVTF), was previously shown to form a noncovalent binding complex with HSP110 at a 1/50 molar ratio and to elicit antitumor immunity in C57BL/6 mice (29). Moreover, the epitope E7 [11][12][13][14][15][16][17][18][19][20] is not only a well-known HLA-A*0201-restricted human CTL epitope of the HPV16 E7 protein that shows highaffinity binding to HLA-A2 in vitro (8,30,31).…”

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confidence: 99%

Cytolytic Activity of the Human Papillomavirus Type 16 E7_11-20Epitope-Specific Cytotoxic T Lymphocyte Is Enhanced by Heat Shock Protein 110 inHLA-A*0201Transgenic Mice

Ding¹,

Ou²,

Ni³

et al. 2013

Clin. Vaccine Immunol.

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e Heat shock proteins (HSPs) have been successfully applied to a broad range of vaccines as biological adjuvants to enhance the immune response. The recently defined HSP110, in particular, exhibits strong protein binding affinity and is capable of enhancing the immunogenicity of protein antigens remarkably more than other HSP family members. In our previous study, we verified that murine HSP110 (mHSP110) significantly enhanced the immune response of a C57BL/6 mouse model to the H-2 d -restricted human papillomavirus (HPV) E7 49-57 epitope (short peptide spanning the 49th to 57th amino acid residues in the E7 protein). To determine whether HSP110 similarly enhances the immunogenicity of human epitope peptides, we used the HLA-A2 transgenic mouse model to investigate the efficacy of the mHSP110 chaperone molecule as an immunoadjuvant of the human HLA-A2-restricted HPV16 E7 11-20 epitope vaccine. Results showed that mHSP110 efficiently formed a noncovalently bound complex with the E7 11-20 epitope. The mHSP110-E7 11-20 complex induced epitope-specific splenocyte proliferation and E7 11-20 -specific gamma interferon (IFN-␥) secretion. Importantly, cytotoxic T lymphocytes primed by the mHSP110-E7 11-20 complex exerted strong cytolytic effects on target T 2 cells pulsed with the E7 11-20 peptide or TC-1 cells transfected with the HLA-A2 gene. In addition, the mHSP110-E7 11-20 complex elicited stronger ex vivo and in vivo antitumor responses than either emulsified complete Freund's adjuvant or HSP70-chaperoned E7 11-20 peptide. These collective data suggest that HSP110 is a promising immunomodulator candidate for peptide-based human cancer vaccines, such as for the HLA-A2-restricted E7 11-20 epitope.C ervical cancer (CaCx) is the second leading cause of cancer deaths among women worldwide. CaCx is strongly associated with human papillomavirus (HPV) infection, particularly HPV types 16 and 18. Several clinical studies have demonstrated constitutive expression of the HPV16 oncoproteins E6 and E7 in the majority of cervical tumor cells (1-4). Since cervical tumors often recur after surgery and/or radiotherapy (5, 6), it is critical to develop prophylactic and therapeutic strategies that completely eliminate the tumor cells. HPV16 cytotoxic T lymphocyte (CTL) epitopes may be good candidates for the development of an effective peptide-based antitumor vaccine (7-9). In fact, studies in animal models have already shown that HPV16-specific CTLs can safely eradicate HPV16-transformed tumor cells in vivo (10).To date, many therapeutic vaccine strategies have been developed targeting the HPV16 E6/E7 proteins (11-14). Among these, the synthetic peptide-based strategies have the particularly remarkable advantages of convenient and low-cost high-throughput preparation and rare occurrences of adverse reactions, including general toxicity, immunosuppression, and autoimmunity (15-17). More importantly, when generating specific CTLs it is possible to select the length of the amino acid sequence that is most suitable for the particular a...

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Exploring the Role of Heat Shock Proteins in the Development of Gastric Cancer

Verma

Sharma

2020

Heat Shock Proteins in Human Diseases

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Heat shock protein 110 improves the anti-tumor effects of the cytotoxic T lymphocyte epitope E7 in mice

Cited by 21 publications

References 59 publications

Prediction and identification of human leukocyte antigen‑A2‑restricted cytotoxic T lymphocyte epitope peptides from the human papillomavirus 58 E7 protein

Prediction and identification of human leukocyte antigen‑A2‑restricted cytotoxic T lymphocyte epitope peptides from the human papillomavirus 58 E7 protein

Cytolytic Activity of the Human Papillomavirus Type 16 E7_11-20Epitope-Specific Cytotoxic T Lymphocyte Is Enhanced by Heat Shock Protein 110 inHLA-A*0201Transgenic Mice

Exploring the Role of Heat Shock Proteins in the Development of Gastric Cancer

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Heat shock protein 110 improves the anti-tumor effects of the cytotoxic T lymphocyte epitope E7 in mice

Cited by 21 publications

References 59 publications

Prediction and identification of human leukocyte antigen‑A2‑restricted cytotoxic T lymphocyte epitope peptides from the human papillomavirus 58 E7 protein

Prediction and identification of human leukocyte antigen‑A2‑restricted cytotoxic T lymphocyte epitope peptides from the human papillomavirus 58 E7 protein

Cytolytic Activity of the Human Papillomavirus Type 16 E711-20Epitope-Specific Cytotoxic T Lymphocyte Is Enhanced by Heat Shock Protein 110 inHLA-A*0201Transgenic Mice

Exploring the Role of Heat Shock Proteins in the Development of Gastric Cancer

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Cytolytic Activity of the Human Papillomavirus Type 16 E7_11-20Epitope-Specific Cytotoxic T Lymphocyte Is Enhanced by Heat Shock Protein 110 inHLA-A*0201Transgenic Mice